How an Air Pollutant Received the Nobel Prize in Medicine

1. A Short History of Nitric Oxide For decades nitric oxide gas was considered as an environmental pollutant. Then in the early 1990's its biological significance was appreciated and in 1992 the prestigious journal Science declared nitric oxide the molecule of the year. The importance of this molecule was confirmed when in 1998 the Nobel Prize for medicine was awarded to scientists working in the field of nitric oxide biological research. It is remarkable that Alfred Nobel, the founder of Nobel Prize, also indirectly contributed to nitric oxide research. He discovered nitroglycerin which besides being an explosive, is also a drug that produces its action within the body by releasing nitric oxide. The remainder of this document will try to explain the medical significance of this molecule as well as the research and development opportunities resulting from this knowledge.

2. What Nitric Oxide Does in the Body Nitric oxide, abbreviated as NO, is a simple gas composed of nitrogen and oxygen atoms. In the body it is generated through the action of enzyme systems called nitric oxide synthase. The enzyme uses a common amino acid, L-arginine, and converts it to NO gas. This process takes place in many cells and tissues. The nitric oxide thus produced then regulates many body functions including: blood pressure, respiration, blood clotting, bacterial killing, cancer prevention, brain and sexual function. Blood vessels continuously generate small amounts of NO that causes the vessels to widen and greatly increases its blood flow. At the same time, some of the NO interacts with blood platelets, the elements in the blood stream responsible for clotting. This causes the platelets to become less reactive and prevent their clotting important blood vessels such as those feeding the brain or heart. In the lung blood vessels, NO improves the amount of oxygen that the lungs deliver to the blood. Remarkably, the very same NO molecule, when generated in much greater quantity is a potent cell killer. An important part of the body's defenses against microbial invasion relies upon the production of NO. Cancer cells can also be killed by NO. In this way NO is a major component of the body's policing against infections and tumors. The process of memory formation within the brain may also be NO dependent. Specific cells within the brain produce NO that then reinforces memory storage. With the importance of NO production in so many cells, even minor abnormalities can produce a variety of devastating diseases. Male sexual function, in the form of penile erection, is regulated by NO. Nitric oxide causes the large blood vessels in the penis to fill with blood thus resulting in an erection.

3. Nitric Oxide and Diseases Hardening of the arteries, or atherosclerosis, is a disease affecting many Canadians. Atherosclerosis and coronary artery disease can produce a heart attack, a common killer in adults. Abnormalities of NO production have been linked to the origin of this disorder. The failure of NO to relax blood vessels and to prevent platelet clots from forming contributes to the progression of this disease. Premature babies may suffer from lung failure resulting in prolonged need for Intensive Care therapy with all its complications. Reduced lung NO production may be part of this underlying disease process. In fact, a part of the treatment of these desperately ill newborns includes giving extra NO through their lungs. Nitric oxide is greatly increased when the body is invaded by bacteria. This increased NO is a defense mechanism but if there is too much NO it may cause significant harm. When this process spirals out of control then septic shock develops. Septic shock is characterized by a loss of blood pressure and poor circulation to the vital organs. Over ¼ million individuals in North America experience this life threatening disease process every year. When blood flow to a portion of the brain is blocked the symptoms of paralysis and loss of speech then result. This condition is typically known as a stroke. Excessive NO released by the affected brain tissue is thought to cause extra cell injury and thus worsen the eventual clinical outcome. Erectile failure results when the blood vessels in the penis are damaged. Recently, an extremely successful medication, Viagra, made headlines worldwide. This medication reinforces the action of NO on penile blood vessels and helps restore erectile function.

4. Capitalizing on the Basic Science Discoveries in Nitric Oxide Biology Even Alfred Nobel eventually needed nitroglycerin therapy to alleviate his angina. Nitroglycerin and its related class of drugs are still one of the safest and most commonly used heart medications. These drugs deliver NO to all organs in the body, even if additional NO is not needed or indeed even if it may even cause unwanted side effects. These side effects may include severe headaches or dangerous falls of blood pressure. Better understanding of the biology of NO may allow development of new NO-based drugs free of unwanted side effects. These drugs may be able to target the damaged tissues with improved selectivity. Fine-tuning of excess NO generation has been hampered by the lack of bedside sensors to measure NO status within the body. Drugs to reduce the excess NO production in septic shock might be desirable if these sensors became widely available. NO gas has been used to treat adults and newborns with impaired blood flow and poor oxygen delivery by the lungs. There is a great demand for a safe technology to measure and deliver this gas. This may be in the Intensive Care setting or the hospital ward setting. This may even be extended to home use. This document highlights just a few selected applications of NO technology. We have not attempted to review the more than 20,000 scientific publications related to NO. Our intention is to increase the awareness of the medical importance of this extraordinary compound. At the turn of the 20th century it is clear that the potential for nitric oxide research is still in its infancy. However it is clear that NO offers great promise for basic, clinical, and commercial development.

Prepared by: M. Radomski, MD, PhD I. Mayers, MD, FRCPC September 23, 1999

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